This invention relates to a method for increasing the transdermal flux of albuterol and to compositions for effecting the method. The compositions of the invention, which greatly increase the transdermal flux of albuterol, comprise albuterol with a combination of 1-dodecyl-azacycloheptan-2-one and urea.
1-Dodecyl-azacycloheptan-2-one is registered under the U.S. Trademark "Azone" and is commercially available from Nelson Research and Development Company, Irvine, Calif.
Compositions and the method for preparation of the compound are disclosed in U.S. Pat. Nos. 3,989,815, and 4,316,893.
1-Dodecyl-azacycloheptan-2-one has properties which enhance the percutaneous absorption of certain chemical agents with which it is incorporated.
The use of suitable amounts of 1-dodecyl-azacycloheptan-2-one as a physiological carrier for topically administering an active agent to a human or animal is also disclosed in these patents, and discussed in Stoughton, Azone.RTM. (1-dodecyl-azacycloheptan-2-one) Enhances Percutaneous Penetration, III International Symposium on Psoriasis, Stanford, (Jul. 13-17, 1981).
UK Pat. No. 1,468,815 discusses the use of urea in the treatment of skin conditions and restrictions on its use because it is unstable in neutral aqueous solution and decomposes, liberating carbon dioxide and ammonia. Urea buffered at a pH of about 2.0 has been tried, however, this very high acid level causes the cream containing said buffered urea to sting on application.
Further, urea, in an aqueous solution when adsorbed onto particles of an inert powder has been found to be sufficiently stable to be formulated into skin creams and other pharmaceutical preparations. U.S. Pat. No. 3,666,863 indicates that urea in aqueous solution has been used to enhance the topical absorption of compounds which have been known to have poor absorption.
The use of urea as a therapeutic agent for the treatment of hyperkeratotic skin conditions is disclosed in U.S. Pat. No. 3,666,863 and UK Pat. No. 1,468,815. In particular, urea is disclosed as being capable of hydrating the skin so as to allow the percutaneous transportation of medication, thus acting as a drug delivery system. A. C. Allenby, et al, Mechanism of Action of Accelerants on Skin Penetration, Brit. J. Dermatol., Suppl. 81 (4), 47-55 (1969).
.alpha..sup.1 -[Tert-butylamino)methyl]-4-hydroxy-m-xylene .alpha.,.alpha.'-diol, also known as albuterol, is useful as a relatively selective beta-2 adrenergic bronchodilator. The rate and extent of albuterol diffusion through skin is slow and insufficient to be therapeutic from simple conventional formulations. This is so because albuterol does not possess the necessary physical-chemical characteristics of a molecule which is best suited for absorption from systemic topical application.